Molecular Mechanisms Program, Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer (CSIC-Universidad de Salamanca), Salamanca, Spain
Université de Paris, Paris Cedex, France; Institut Jacques Monod, Université de Paris, Paris, France
Fernando Sánchez-Sáez
Molecular Mechanisms Program, Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer (CSIC-Universidad de Salamanca), Salamanca, Spain
Yazmine B Condezo
Molecular Mechanisms Program, Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer (CSIC-Universidad de Salamanca), Salamanca, Spain
Dirk G de Rooij
Reproductive Biology Group, Division of Developmental Biology, Department of Biology, Faculty of Science, Utrecht University, Utrecht, Netherlands
Laura Gómez-H
Molecular Mechanisms Program, Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer (CSIC-Universidad de Salamanca), Salamanca, Spain
Molecular Mechanisms Program, Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer (CSIC-Universidad de Salamanca), Salamanca, Spain
Anne Laure Todeschini
Université de Paris, Paris Cedex, France; Institut Jacques Monod, Université de Paris, Paris, France
Paloma Duque
Molecular Mechanisms Program, Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer (CSIC-Universidad de Salamanca), Salamanca, Spain
Manuel Adolfo Sánchez-Martin
Transgenic Facility, Nucleus platform, Universidad de Salamanca, Salamanca, Spain; Departamento de Medicina, Universidad de Salamanca, Salamanca, Spain
Stavit A Shalev
The Genetic Institute, "Emek" Medical Center, Afula, Israel; Bruce and Ruth Rappaport Faculty of Medicine, Technion, Haifa, Israel
Elena Llano
Molecular Mechanisms Program, Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer (CSIC-Universidad de Salamanca), Salamanca, Spain; Departamento de Fisiología y Farmacología, Universidad de Salamanca, Salamanca, Spain
Université de Paris, Paris Cedex, France; Institut Jacques Monod, Université de Paris, Paris, France; Université Paris-Saclay, Institut de Biologie F. Jacob, Commissariat à l’Energie Atomique, Fontenay aux Roses, France
Molecular Mechanisms Program, Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer (CSIC-Universidad de Salamanca), Salamanca, Spain
Primary Ovarian Insufficiency (POI) is a major cause of infertility, but its etiology remains poorly understood. Using whole-exome sequencing in a family with three cases of POI, we identified the candidate missense variant S167L in HSF2BP, an essential meiotic gene. Functional analysis of the HSF2BP-S167L variant in mouse showed that it behaves as a hypomorphic allele compared to a new loss-of-function (knock-out) mouse model. Hsf2bpS167L/S167L females show reduced fertility with smaller litter sizes. To obtain mechanistic insights, we identified C19ORF57/BRME1 as a strong interactor and stabilizer of HSF2BP and showed that the BRME1/HSF2BP protein complex co-immunoprecipitates with BRCA2, RAD51, RPA and PALB2. Meiocytes bearing the HSF2BP-S167L variant showed a strongly decreased staining of both HSF2BP and BRME1 at the recombination nodules and a reduced number of the foci formed by the recombinases RAD51/DMC1, thus leading to a lower frequency of crossovers. Our results provide insights into the molecular mechanism of HSF2BP-S167L in human ovarian insufficiency and sub(in)fertility.
